Broadening the Applicability of CAR-T Immunotherapy to Treat the Untreatable

Render of t-cells. Courtesy 2019 Fotolia.
Render of t-cells. Courtesy 2019 Fotolia.

In the early 2000s, chimeric antigen receptor T (CAR-T) cells emerged on the scene with promise as a revolutionary cancer treatment. However, several key challenges and, in particular, downsides related to manufacturing, continue to hamper broad adoption of this therapeutic approach.

In addition, existing CAR-T cell therapies are based on autologous approaches (i.e. using the own patient’s cells), meaning that product has to be individually made for each patient.[1] This presents a true challenge in terms of scalability and having the product available for a large patient population.

Traditionally, CAR-Ts derive from a single disease-specific antibody and thus, by design, only recognize one specific antigen (Figure 1.0). As a consequence, only a small subset of patients with any given cancer may be suited for the treatment. Furthermore, tumors develop immune evasion strategies over time rendering the specific CAR-T used in the first place no longer efficient. An extra layer of difficulty comes with solid cancers where access to antigens is more difficult, making these types of tumors harder to treat.

Figure 1.0: Traditionally, CAR-Ts derive from a single disease-specific antibody and thus, by design, only recognize one specific antigen.

In addition to design challenges, adapting a CAR-T cell manufacturing process from a single academic center to a large-scale multi-site manufacturing center bears inherent challenges. Scaling out production means developing processes consistent across many collection, manufacturing, and treatment sites.

Commercial success will thus only be achievable if the entire product chain, including the processes of the hospital where the patient is taken care of, is well understood and mastered.

In addition, time is of the essence for patients with late-stage or quickly progressing diseases which, on average, takes up to three weeks to generate autologous CAR-T cells. While these challenges may seem like monumental tasks for companies to overcome, there are newer strategies that can be implemented in the development process to potentially help address some of these limitations.

The key to unlocking a broader CAR-T
Getting away from the “one CAR-T / one cancer” paradigm will help unleash the true potential of this technology. One strategy is exploring an alternative approach centered around CARs with broader applicability, such as the ones utilizing NKG2D (natural killer group 2 member D), an activating receptor naturally expressed on natural killer (NK) cells (Figure 2.0). This receptor plays an important role in the innate immune system’s ability to protect against infections and cancer. It binds to eight different ligands induced in response to stress, such as the genomic stress seen in cancer. These ligands have been found expressed in 80% of cancers, hematologic and solid alike. NKG2D-based CAR-T product candidates are developed by Celyad in the autologous settings with CYAD-01.

CYAD-01 is being explored in two hematologic cancers (relapsed/refractory acute myeloid leukemia [r/r AML] and myelodysplastic syndrome, as well as in one solid tumor type, metastatic colorectal cancer (mCRC).

These exploratory studies help validate the NKG2D-based approach in cancer-types where tumor-specific CAR-T strategies have shown early promise such as hematologic cancers. On the other hand, studies in mCRC are among the earliest tests of CAR-T effectiveness in solid tumors. In a study with no chemotherapy preconditioning, CYAD-01 was well-tolerated and showed early signs of efficacy, evidenced by antileukemic activity in patients with r/r AML. In solid tumors, CYAD-01 looks well-tolerated and demonstrated a clinical benefit with patients experiencing disease stabilization across multiple dose levels of the treatment.

Figure 2.0: … one strategy is exploring an alternative approach centered around CARs with broader applicability, such as the ones utilizing NKG2D (natural killer group 2 member D), an activating receptor naturally expressed on natural killer (NK) cells.

Going ‘off of the shelf’
Another newer approach that may circumvent some of the issues mentioned above is developing allogeneic CAR-T cell therapies. With allogeneic CAR-Ts, the source of T-cells used to generate the CAR-T product is derived from a healthy donor, as opposed to deriving them from a cancer patients’ own T-cells.

The biggest barrier to developing allogeneic therapies is overcoming graft-versus-host disease (GvHD), in which the donor T-cells recognize the patient’s cells as foreign and attack the healthy tissue. GvHD is mediated by signaling through the T-Cell receptor complex (TCR).

Celyad’s non gene edited NKG2D-based allogeneic CAR-T product candidate CYAD-101 utilizes a small peptide called T-cell receptor Inhibitory Molecule (TIM) that interferes with the ability of the T-cell receptor to transmit the signal responsible for GvHD. Early clinical data from the alloSHRINK trial (NCT03692429) of CYAD-101 in patients with mCRC showed no evidence of GvHD in six patients treated, which we believe is the first clinical evidence of safety with an allogeneic CAR-T in solid tumors.

Expanding on these ‘off-the-shelf’ allogeneic therapies, Celyad developed an shRNA platform to manufacture non-gene edited allogeneic CAR-T cells that have the major advantage of using a single vector approach rendering the production process simpler. Single vector ‘off-the-shelf’ therapies could potentially allow the rapid manufacturing of CAR-T therapies in advance to treat a large number of patients and also get these treatments to patients with fast-progressing cancers quicker than personalized autologous cell therapies.

Turning to in-house manufacturing to speed up efficiency
Another key challenge to implementing any CAR-T cell-based therapy is the manufacture and distribution of the cells. One possible way to circumvent this challenge is by developing in-house manufacturing expertise to independently improve and optimize a company’s streamlined processes. This would result in the seamless and efficient reproduction of materials to advance a company’s pipeline from the preclinical stage through to clinical evaluation and eventually commercialization.

With rapidly progressing or late-stage cancers, every minute counts. Reducing the overall production time for cell therapies can greatly increase patient access, with every day saved making an impact. For example, Celyad developed the OptimAb production method to produce CAR-T cells in a shortened eight-day process. Further refinement of the production timeline for CAR-Ts will have a greatly positive impact on patient outcomes.

CAR-Ts for today, tomorrow and beyond
While CAR-Ts have been limited by several factors including high production costs and a lack of therapies applicable to a broad range of cancer types, companies are starting to explore new means to help unveil the true potential of CAR-Ts. One example is the development of immunotherapies utilizing the receptor NKG2D that binds stress-induced ligands and thus enhances the detection and destruction of tumor cells by CAR-T cells.

Additional advancements are driving the evolution of CAR-T therapies toward ‘off-the-shelf’ – or allogeneic T-cells – which can be developed in advance from healthy donor cells to be available for multiple patients on an as-needed basis. These cells are modified to prevent or reduce the possibility of patients developing GvHD, the first hurdle to pass in order to kick off development of ‘off-the-shelf’ CAR-T therapies.

By incorporating new technological developments and by continuing to improve manufacturing processes, there is great hope that these advances can overcome the current limitations hindering wide CAR-T adoption and make this effective new treatment an option for patients in need.

Clinical trials
alloSHRINK – Standard cHemotherapy Regimen and Immunotherapy With Allogeneic NKG2D-based CYAD-101 Chimeric Antigen Receptor T-cells (alloSHRINK) – NCT03692429

Bagley SJ, O’Rourke DM. Clinical investigation of CAR T cells for solid tumors: lessons learned and future directions. Pharmacol Ther. 2019 Oct 16:107419. doi: 10.1016/j.pharmthera.2019.107419. [Pubmed][Article]